Abstract C-reactive protein (CRP) serves as a pivotal marker of systemic inflammation, yet its genetic architecture has predominantly been explored within European populations. Our multi-ancestry sequencing-based genome-wide association study (seqGWAS) meta-analysis encompasses 447,369 Europeans, 10,389 Africans, 9685 Asians, and 9200 Hispanics in the discovery set, and 23,521 Europeans, 7160 Africans, 771 Asians, and 5178 Hispanics in the replication set. We identify 113 independent association signals (P discovery ≤ 5 × 10−9 and P replication ≤ 0.05), including 21 loci that passed the conditional analysis, among which 3 are European-specific. Cross ancestry fine-mapping pinpoints 19 of 113 independent signals within the 95% credible set. Functional annotation reveals significant enrichment in blood tissue, H3K27me3 histone marks, and exonic regions. Leveraging the Polygenic Priority Score (PoPS) and gene-based analyses, we implicate 151 genes as potential regulators of CRP levels, 55 of which have not been previously reported. Among these, 17 genes and four proteins show causal evidence or strong colocalization with CRP-related pathologies.